Our funded U01 project in the AMP-AD consortium had the overarching aim of identifying therapeutic targets within innate immunity pathways. In the previous funding period, we made significant progress and met all milestones of our U01. We have nominated multiple targets in the immune system, and these targets are at various stages of validation. Nevertheless, key gaps in our understanding impede transformation of the collective AMP-AD knowledge to validated therapeutic targets. Despite identification of numerous perturbed transcriptional networks, some enriched for Alzheimer's disease (AD) risk genes, key tractable targets in these networks are not unequivocally identified and validated. Further, whether the observed transcriptional changes are a simple consequence of disease or actually, play a role in the pathologic cascade has, typically, not been determined. Finally, the direction of molecular changes that is beneficial vs. detrimental has, in most cases of nominated targets, not been established. To overcome these gaps in knowledge, we will i) leverage unique aspects of our existing data and tools along with data and analyses generated by the larger AMP-AD consortia, ii) generate complementary new data, and iii) apply innovative analytic approaches. Notably, our ability to perform comparative analysis of control (no pathology), PathAg, (Pathologic Aging, amyloid+), AD (tau+, amyloid+) and PSP (progressive supranuclear palsy, tau+) enables a framework to identify therapeutic targets that play a role in the transition to different disease stages of AD. Further, comparisons between two brain regions (TCX=affected and CER=largely spared in AD) and between AD and PSP can help distinguish whether the molecular changes identified are likely a cause or consequence of pathology. In this renewal application, we propose to: i) refine and genetically validate therapeutic targets ii) identify molecular mechanisms and targets that mediate disease transition from control to PathAg to AD iii) define the drug target mechanism(s) iv) evaluate select prioritized targets in relevant models, v) continue the collaboration with all AMP-AD partners to promote consortium wide-target validation and vi) share our data openly with the larger scientific community. These studies will include the final phase of modeling studies for more than 20 immune targets identified in the original grant cycle with a goal of making firm go, no-go, decisions on select targets. These studies will enable us to i) provide biologic insight into the mechanism of action of the proposed targets and ii) inform on the direction of change needed for therapeutic benefit. Identification of key targets that drive the transition from control to amyloid positivity, and then to tau pathology and neurodegeneration will enable us to propose alignments of future clinical testing of therapeutics that manipulate these targets in appropriate disease stages-increasing the likelihood to achieve clinical efficacy and avoiding costly testing of an agent in an intent to treat population that is unlikely to benefit.